Recent studies in isolated arterial preparations including some in coronary arteries have demonstrated an obligatory role for endothelial cells in vascular smooth muscle relaxation by certain endogenous vasoactive substances. In some instances, removal of the endothelium transforms a normal vascular relaxant response to one of those agents into a dose dependent constrictor response. These observations in isolated vessels suggest that endothelial cells could play an important role in the pathophysiology of various cardiovascular disease states. The overall objective of the proposed research will be to determine the role of the endothelium in modulating vascular reactivity in the intact coronary circulation of the dog. The major hypothesis to be tested is that mechanical or ischemic damage to the coronary vascular endothelium will attenuate vasodilator responses or potentiate vasoconstrictor responses to certain endogenous neurohumoral stimuli. The specific aims will be 1) to assess the vasomotor responses of large epicardial coronary arteries to neurohumoral stimuli before and after mechanical disruption of the endothelium and 2) to evaluate the effects of intimal damage produced by selective segmental ischemia of epicardial arteries on vasomotor responses to neurohumoral stimuli. These studies will be performed in an open chest anesthetized dog model which employs constant pressure perfusion of the coronary circulation. Epicardial coronary artery diameter will be measured instantaneously using an ultrasonic dimension gauge and miniature sonomicrometer crystals sewn to the outer adventitia of the artery. Coronary blood flow will be measured with an electromagnetic flow probe in the perfusion circuit. Dose response curves to intracoronary infusions of neurohumoral agents will be obtained before and after mechanical or ischemic disruption of the endothelium. Information regarding the role of the endothelium in modulating coronary vascular reactivty in vivo will be important in better understanding the physiological control and pharmacological modification of the coronary circulation. In addition, these studies are likely to provide new insight into the mechanism(s) of coronary vasospasm in pathophysiologic states which result in endothelial damage.